Alkyl substituted benzyl pyrimidines

ABSTRACT

ANTIMALARIAL AND ANTIBACTERIAL COMPOUNDS OF THE FORMULA   2,6-DI(H2N-),5-((3-R1,4-R2,5-R3-PHENYL)-CH2-)PYRIMIDINE   WHERE R1 AND R3 ARE THE SAME OR DIFFERENT AND EACH IS AN ALKYL GROUP HAVING FROM 2 TO 4 CARBON ATOMS, AND R2 IS AN ALKYL OR ALKOXY GROUP HAVING FROM 1 TO 12 CARBON ATOMS.

United States Patent US. Cl. 260-256.4 N 11 Claims ABSTRACT OF THE DISCLOSURE Antimalarial and antibacterial compounds of the formula R1 RL@CHI 0 NH2 where R and R are the same or different and each is an alkyl group having from 2 to 4 carbon atoms, and R is an alkyl or alkoxy group having from 1 to 12 carbon atoms.

This invention relates to 2,4-diamino-5-benzylpyrimidines, more particularly to such compounds which have antimalarial and/or antibacterial activity.

In the past, it was generally assumed that 2,4-diamino- S-benzylpyrimidines only have relevant antimalarial activities when electron withdrawing substituents are present in the pand/or m-positions and/or when the 6-position in the pyrimidine ring is substituted by a lower alkyl group (Roth et al., Journal of Medicinal and Pharmaceutical Chemistry, page 1103, 1962). For example, 2,4-diamino- 5-(4-chlorobenzyl)-6-methylpyrimidine has considerably enchanced antimalarial activity over the unsubstituted 2, 4-diamino-S-benzylpyrimidine. Attempts to enchance the antimalarial activities of 2,4-diamino-S-benzylpyrimidines by substituting the phenyl ring with alkyl substituents have, in the past, not met with much success.

Moreover, antibacterial activity has been found to be maximal in 2,4-diamino-5-benzyl-6-unsubstituted pyrimidines having alkoxy substituents in the 3,4- and 3,4,5 positions of the benzene ring, Trimethoprim, 2,4-diamino- 5-(3',4', -trimethoxybenzyl) pyrimidine (U.S. Pat. 2,909;- 522), is especially notable.

The applicants have now surprisingly discovered a novel class of compounds, containing at least two alkyl groups in the benzene ring, which have superior antibacterial and/ or antimalarial properties.

Accordingly the present invention provides a compound of Formula I:

wherein R and R are the same or different and each is an alkyl group having from 2 to 4 carbon atoms, and R is an alkyl or alkoxy group having from 1 to 12 carbon atoms.

The alkyl groups R and R having 2 to 4 carbon atoms are ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, isobtuyl, and t-butyl. It is particularly preferred that the R and R substituents are identical.

The group R is preferably an alkyl or alkoxy group containing from 1 to 8 carbon atoms. Most desirably alkyl groups have from 1 to 4 carbon atoms. It is particularly preferred that R is a methoxy, ethoXy, ethyl, propyl or butyl group.

3,772,289 Patented Nov. 13, 1973 ice The especially preferred compounds of the invention, having notable advantageous antimalarial and antibacterial properties, are 2,4-diamino-5-(3,4,5-triethylbenzyl)- and 2,4-diamino-5-(3',5'-diethyl-4'-methoxybenzyl)pyrimidine.

In another aspect of the invention there is also provided a method of preparing a compound of general Formula I which comprises reacting guanidine with a compound of general Formula 11:

i ON

R z Y (II) wherein R R and R are as defined in Formula I, and

either:

(a) X and Y taken together represent an additional bond when Z represents: (i) the group NR R which is an aliphatic, heterocyclic, or aromatic amino group wherein R and R cannot both be hydrogen, or (ii) an alkoxy group; or

(b) X is an hydrogen atom when Y and Z are both alkoxy groups, each containing from 1 to 4 carbon atoms.

The group NR R preferably represents a secondary anilino group or a morpholino group. The alkoXy group is preferably a methoxy group. Such processes are described in copending US. patent application :Ser. Nos. 16,605 and 16,606 both filed on Mar. 4, 1970. Application Ser. No. 16,606 having issued as US. Pat. No. 3,697,512, and application Ser. No. 16,605 having been abandoned, and in United Kingdom patent specification Nos. 957,797, 1,133,766, and 1,142,654. For instance, the reaction with guanidine is conveniently effected in a lower alkanol solvent, for example, methol, ethanol or isopropanol, at elevated temperatures in the presence of a base. It is particularly preferred that the reaction be carried out at the reflux temperature of the reaction mixture but useful reaction rates have been obtained at temperatures down to room temperature. It has been found that the reaction with guanidine of compounds of Formula II wherein X and Y taken together represent an additional bond and Z represents the group NR R can be effected in the absence of a base, if the guanidine is in the form of the carbonate in a polar aprotic solvent, e.g., dimethyl sulphoxide or hexai on R3 (III) wherein R is an alkyl group, preferably having from 1 to 4 carbon atoms, with dimethyl sulphoxide or dimethyl sulphone, under strongly basic conditions.

(b) Reducing the -C=O bond in the product to a CHOH group, and then (0) Reacting the hydrogenated product with a substituted propionitrile of Formula IV:

3 wherein R and R are as defined in (II) and wherein R and R cannot both be hydrogen.

Any base which is strong enough to provide the methylsulphinyl or methylsulphonyl carbanion in an adequate quantity is suitable for step (a) of the above reaction sequence. Preferably the step (a) is carried out in a solvent with the base supplied as sodamide or sodium hydride from which ammonia or hydrogen is released with a complete conversion to the above mentioned anions.

The reduction of the carbonyl group in step (b) can conveniently be effected using a reducing agent reacting in solution, i.e., in a homogeneous system. Conveniently, complex hydrides such as those of boron compatible with alcoholic or aqueous solvents and aluminum compatible with ethers or benzene may be employed, for instance, in the form of a suitable alkali metal, e.g., sodium or lithium, salt. Step (c) is preferably carried out in the presence of a base which is desirably a hydroxide or alkoxide, or example, a methoxide or a tertiary butoxide ion, or the methylsulphinyl carbanion in a dimethyl sulphoxide medium. The solvent is a polar non-aqueous solvent compatible with and dissolving both reactants. It may be an alkanol, for example, methanol or ethanol, but is preferably a polar aprotic solvent such as dimethyl sulphoxide, N,N-dimethylacetamide or hexamethylphosphoramide.

Another method of preparing the compound of Formula II in which X and Y taken together represent an additional bond and Z is an NR R group, comprises reacting a corresponding benzaldehyde of general Formula V:

with a compound of Formula IV, as hereinbefore defined, in the presence of a base in a polar solvent compatible with and dissolving both reactants.

Preferred are the polar, aprotic solvents such as hexamethyl phosphoramide and N,N-dimethylacetamide, but best results have been obtained with dimethyl sulphoxide as the solvent.

Bases which may be used for the reaction include the hydroxides, the alkoxides, for example, methoxide or tertiary butoxide, and the methylsulphinyl carbanion used in association with a suitable cation such as an alkali metal (e.g., sodium or potassium).

4-alkoxybenzaldehydes having al-kyl substitucnts in the 3,5-positions may be prepared by reaction of suitable alkylated phenols with dimethylformamide and phosphorus oxychloride (Vilsmeicr-Haach Reaction) or with hexamethylenetetramine (as reported in Organic Synthesis, Collective vol. IV, p. 866, or Chemical Abstracts 56, 1l471b, and 57, 14981i and 57, 16459i) followed by alkylation of the phenolic group with such alkylating agents as al'kyl halide or dialkyl sulfate.

A further method of preparing a compound of Formula II wherein X and Y taken together represent an additional bond and Z is an NR R group comprises reacting a ,3- hydroxy-a-benzylacrylonitrile of Formula VI:

with an amine of formula HNR R wherein R R R R and R are as previously defined.

If a solvent is used it should be a non-aqueous solvent such as benzene or an alkanol, e.g., ethanol. It has been found convenient to carry out the reaction at elevated temperatures, particularly at reflux temperatures. Such fi-hydroxy derivatives may be conveniently obtained by the acid hydrolysis of less preferred corresponding ,8- amino derivatives.

A further method of preparing the compound of Formula II wherein X and Y represent an additional bond and Z is an NR R group which is a secondary amino group or a tertiary amino group, comprises reacting a compound of Formula VII:

with the appropriate primary amine or secondary amine, wherein R R R R R and R are as defined above, in the presence of a base and an alcohol.

The alkanol is, for example, methanol and the base is, for example, an alkoxide such as a methoxide.

A further method of preparing the compound of Formula II wherein X and Y represent an additional bond and wherein Z is an NR R group other than an anilino group, comprises isomeriziug a compound of General Formula VIII:

R vrrr wherein R R R R and R are as defined above, with a base in a polar, aprotic solvent.

Suitable bases and polar aprotic solvents are as hereinbefore described with reference to other reactions, the most preferred solvent again being dimethyl sulphoxide and the most convenient bases being the methoxide and t-butoxide anions.

Yet a further method for preparing compounds of Formula H where X and Y together represent an additional bond and wherein Z represents the group NR' R which is a secondary anilino group optionally substituted in the phenyl ring, comprises reacting the corresponding benzaldehyde of Formula V with the corresponding fl-anilinopropionitrile of Formula IV. Preferably, the reaction is carried out in a polar solvent compatible with and dissolving the reactants in the presence of a base. Conveniently an alkanol may be used for the purpose, and the reaction is desirably carried out at elevated temperatures, say between 40 and C. Bases already listed in relation to the other preparatory methods are again applicable, and may, for instance, be used in a quantity greater than 1 molar equivalent calculated on the aldehyde, especially when the reaction is carried out at the lower end of the indicated temperature range.

The above group of ,9 anilino 0c benzyl acrylonitriles can also be prepared by a method which comprises reacting the corresponding aniline, generally in the form of an acid addition salt, with a corresponding compound of Formula II carrying for Z an amino substituent which has, as the free amine HNR R a pKa value higher by at least about 3 to 4 units than that of the aniline used for the reaction. For instance, a morpholino substituent may, in this manner, be directly replaced by an anilino substituent, morpholine having a pKa value of about 8.6 and the aniline generally about 4 to 5. Preferably the reaction is carried out in a polar non-aqueous solvent system, for instance, ethanol or glacial acetic acid, at reflux temperatures.

A preferred method of preparation of compounds of General Formula II, wherein X and Y together represent an additional bond and Z represents an anilino group, comprises therefore reacting a compound of General Formula V with fl-morpholinopropionitrile in the presence of dimethyl sulphoxide and methoxide ions to form the Compound IX:

CHa-O and then reacting this with a salt of aniline to form the Compound X:

The conversion of the fl-morpholinoacrylonitrile to the fl-anilinoacrylonitrile can be carried out using an alkanol, for example, isopropanol, as solvent under reflux conditions.

Compounds of General Formula II wherein X and Y taken together represent an additional bond and wherein Z is an alkoxy group can be prepared by reacting a compound of Formula V with a ,B-alkoxypropionitrile.

The reaction can be carried out in the presence of a strongly basic catalyst such as alkoxide or amide ions. The use of amide ions, for example, from sodamide require a non-hydroxylic solvent. In practice, the reaction is best carried out in solution in a lower alkanol using, as catalyst, the sodium derivative of that alcohol. During the reaction water is produced. Generally it is best to remove it, for example, by azeotropic distillation or by adding a reagent such as magnesium methoxide.

Compounds of General Formula II wherein X represents a hydrogen atom and Y and Z represent alkoxy groups may be formed by treating either compound of General Formulae VII or XI:

wherein R R R and R are as previously defined, with an alkoxide anion (R 0), for example, methoxide, in association with a suitable cation, such as an alkali metal, e.g., sodium, or an quaternary ammonium, in a medium comprising the corresponding alkanol; R being preferably a methyl group.

These reactions should be carried out utilizing substantially anhydrous conditions. The solvent used is preferably the appropriate alkanol itself.

Such compounds of General Formula H wherein X is a hydrogen and Y and Z both represent alkoxy groups can also be prepared by reacting a benzaldehyde of Formula V with a corresponding B-alkoxyacrylonitrile and then reducing the intermediable abenzylidene-;3,,8-dialkoxypropionitrile product with hydrogen.

Very mild reaction conditions are utilized to ensure that product losses at each stage are low. The reduction of the product with hydrogen can conveniently be carried out using an alkanol having from 1 to 4 carbon atoms, e.g., methanol or ethanol, as a solvent and using a supported catalyst, for example, commercial palladized charcoal. The reaction of the benzaldehyde (V) with the ,6- alkoxyacrylonitrile is carried out in the presence of a basic catalyst which is conveniently and satisfactorily an alkoxide ion having from 1 to 4 carbon atoms. This prepa'ration conveniently takes place in methanol or ethanol as the solvent.

It is believed that the compounds of Formula II are novel and, accordingly, in a further aspect of the invention there are provided the novel intermediates of Formula II.

The pyrimidines of Formula I can also be prepared by reacting a compound of Formula XII:

R1 R -@omono0m I CHO s (XII) in which R is an alkyl group preferably having from 1 to 5 carbon atoms and wherein R R and R are as previously defined, with guanidine to form a compound of Formula XIII:

IIU on R on, Q NH:

-N R3 (XIII) and then clorinating and aminating the hydroxyl group. The hydroxyl group may be chlorinated by heating the compound in phosphoryl chloride. The chloro group so formed may be converted to an amino group by heating the chlorinated compound in alcoholic ammonia under pressure at to C.

Compounds of Formula I in which R is an alkoxy group can be prepared by alkylating a compound of Formula XIV:

R1 NH,

N 0- C) CH; 0 NHi -N it (XIV) wherein R and R are as previously defined, with a compound of formula R Q wherein R is an alkyl group containing from 1 to 12 carbon atoms and Q is a reactive atom or group.

The alkylation of the 4'OH group may be carried out by reaction with an alkyl halide in a polar solvent such as an alkanol containing from 1 to 4 carbon atoms or dimethyl sulphoxide in the presence of a base such as sodium methoxide or potassium hydroxide. Other alkylating agents such as dimethyl sulphate may be used.

The compounds of Formula XIV may be prepared by reacting a Mannich base of Formula XV:

I i. (XV) wherein X is a secondary amino group, with 2,4-diaminopyrimidine under basic conditions.

Another method of preparing a compound of Formula XIV comprises removing the R 8 group from the compound of Formula XVI:

by reacting the Mannich base of Formula XV with a substituted pyrimidine of Formula XVH:

(XVII) The secondary amino group X functions as a leaving group and is not part of the final product; therefore, its nature is not critical. Suitable secondary amino groups are dialkylamino, pyrrolidino, piperidino, morpholino, N- alkylpiperazino; dimethylamino is preferred since the amine is volatile, thus making it possible to follow the reaction by trapping evolved dimethylamine.

The reaction of the 2,4-diaminopyrimidine or 2,4-diamino-6-alkylthiopyrimidine with the Mannich base of Formula XV wherein X represents a dialkylamino group, e.g., dimethylamino group, may be carried out at an elevated temperature of 100 to 200 C., preferably 110- 160 C. in a polar solvent having a boiling point of at least 100 C., and under an inert atmosphere such as nitrogen. Solvents such as dimethylformamide, water, cyclohexanol, pentanol, ethylene glycol, and 2-methoxyethanol are suitable. It is preferable to add a basic catalyst such as sodium methoxide or potassium hydroxide to increase the rate of reaction.

It is also possible to prepare the compounds of Formula I by removing the R 8 group from a compound of Formula XVIII:

wherein R R R and R are as previously defined, using, for example, Raney nickel.

The compounds of Formula I may moreover be prepared by reductive cleavage of the halogen atom from a compound of Formula XIX:

R Ha (XIX) wherein Ha is a halogen atom, preferably a chloro atom, and R R and R are as previously defined. The cleavage is conveniently effected using zinc in an alkaline medium, or by catalytic hydrogenation using, for exmple, palladized charcoal, desirably in the presence of an acid acceptor such as magnesium oxide or sodium carbonate. The compounds of Formula XIX may be prepared by reacting an appropriate benzyl chloride with a cyanoacetic acid alkyl ester, preferably in an alcoholic alkaline alkoxide medium; condensing the formed nitrile with guanidine; and reacting the obtained 2,4-diamino-5-benzyl-6- hyroxy-pyrimidine with a halogenating agent such as phosphorus oxychloride. The intermediate nitrile may also be obtained by reacting an appropriate benzaldehyde with the cyanoacetic acid alkyl ester, and reducing the formed cinnamic derivative.

A preferred method of preparing the Compounds III wherein R and R are identical alkyl groups comprises:

(1) Alkylating an appropriately para-substituted acetophenone, for example, para-ethyl substituted acetophenone, at the 3- and S-positions in the benzene ring using the Friedel-Crafts reaction with an alkyl halide containing from 2 to 4 carbon atoms;

(2) Oxidising the alkylated acetophenone so obtained to the corresponding benzoic acid; and then (3) Esterifying the benzoic acid.

The Friedel-Crafts alkylation proceeds unexpectedly well with 4-alkylated acetophenones.

If it is desired to prepare compounds of Formula Il'I in which R and R are not identical, a mono-alkylated psubstituted acetophenone can be prepared by a mild Friedel-Crafts reaction, for example, and subjected to further Friedel-Crafts alkylation utilising a different alkyl halide. For example, if it is desired to form a 3,4-diallgyl- S-ethyl compound, the 3,4-dialkyl groups being other than ethyl, it is possible to alkylate the para-alkyl acetophenone with an alkyl halide using the Friedel-Crafts reaction to yield 3,4-dialkyl acetophenone. The product is isolated from other by-products by known techniques, e.g., fractional distillation, then further alkylated with ethyl bromide to form the 3,4-dialkyl-S-ethylacetophenone which can subsequently be converted to a corresponding compound of Formula III as hereinbefore described.

The oxidation of the substituted acetophenones to the benzoic acids is preferably carried out using hypochlorite or hypobromite salts. The use of hypochlorites, for example, sodium hypochlorite, is convenient because of their cheapness and also because the reaction works better.

The Friedel-Crafts alkylation may also be carried out on the unsubstituted acetophenone but it has been found that the alkylation proceeds unexpectedly Well with the 4-alkyl substituted acetophenones.

The substituted benzoic acid, formed after step (2) of the above method may be converted to the aldehyde (V) by reaction with thionyl chloride followed by Rosenmund reduction.

It is believed that the benzoate (III), the benzaldehyde (V), the ester (XII), and the pyrimidines (XIII), (XIV), (XVI), and (XVIII) are novel compounds and are therefore provided in further aspects of the invention.

In a further aspect of the invention there is provided a pharmaceutical composition or preparation which comprises a compound of Formula I, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier therefor, or in an effective unit dosage form. As used herein, the term effective unit dosage is denoted to mean a predetermined antimalarial or antibacterial amount sufficient to be effective against the organism in vivo. Pharmaceutically acceptable carriers are materials recommended for the purpose of administering the medicament. These may be liquid, solid or gaseous materials, which are otherwise inert or medically acceptable and are compatible with the active ingreclients.

These pharmaceutical compositions may be given parenterally, orally, used as a suppository, applied as an ophthalmic solution, or applied topically as an ointment, cream, or powder.

"For oral administration, fine powders or granules may contain diluting, dispensing and/or surface active agents, and maybe presented in a draught, in water or in a syrup, in capsules or sachets in the dry state or in a nonaqueous suspension, wherein suspending agents may be included, in tablets, when binders and lubricants may be included, or in a suspension in water or a syrup. Where desirable or necessary, flavouring, preserving, suspending, thickening or emulsifying agents can be included.

For parenteral administration, the compounds may be presentedin aqueous injection solutions which may contain antioxidants or buffers.

As stated above, free base or a salt thereof may be administered in its pure form unassociated with other additives in which case a capsule or sachet is the preferred carrier.

Alternatively the active compound may be presented in a pure form as an effective unit dosage, for instance, compressed as a tablet or the like.

When salts of the tri-substituted benzyl pyrimidines of Formula I are used, the anions which are preferred are those devoid of inherent toxicity. Salts of the following acids are preferred: hydrochloric, phosphoric, lactic, citric, pyruvic, acetic, succinic, fumaric, and oxaloacetic acids. However, toxic salts of the benzyl pyrimidines are useful as they can be converted, for example, by double decomposition with a salt having a non-toxic anion, to a nontoxic form. The salts may be prepared generally by reaction of the pyrimidines with acids.

It may be advantageous to include the compounds of this invention in a pharmaceutical composition which may include other active ingredients such as sulphonamides, e.g., sulfadoxine, sulfadiazine, sulfaguanidine, or sulphamethoxazole, which are known to act synergistically with 2,4-diamino-S-benzylpyrimidines; and/or medicinally inert ingredients, e.g., solid and liquid diluents such as lactose, glucose, starch, or calcium phosphate for tablets or capsules; olive oil or ethyl oleate for soft capsules; and water or vegetable oil for suspensions or emulsions: lubricating agents such as talc or magnesium stearate; gelling agents such as colloidal clays: thickening agents such as gum tragacanth or sodium alginate: and other therapeutically acceptable accessory ingredients such as humectants, preservatives, buffers, and antioxidants which are useful as carriers in such formulations.

Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of the active ingredient which is effective at such dosage or as a multiple of the same, for instance, units containing 2.5 mg. to 500 mg., preferably 10 mg. to 150 mg., usually around 30 to 100 mg.

Still another aspect of the present invention provides a method of treating bacterial and protozoal infections in mammals by the administration of an effective antiprotozoal or antibacterial amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, or a formulation as hereinbefore defined.

As indicated above, the tri-substituted benzylpyrimidines of Formula I are generally useful in treating such infections by topical application to surface infections or by oral administration or injection for the treatmentof such internal infections as those caused by E. coll, B. proteus, K. pneumoniae. They are extremely active against P. berghei in mice. Preferably, 2,4-diamino-5-(3',4,5-triethylbenzyl)pyrimidine or 2,4-diamin-5-(3',5'-diethyl-4- methoxybenzyl)pyrimidine is administered orally in tablet or capsule form at a dose of from 1 mg./kg. to 30 mg./ kg. per day. The dose range for adult humans is generally from 25 to 1,000 mg./day, preferably 50 to 300 mg./day, frequently around 150 to 200 mg.

EXAMPLE 1 3,4,5-triethylbenzoic acid was esterified to the methyl derivative in refluxing methanol containing hydrogen chloride. A 67% by weight suspension (1 gram) of sodium hydride in mineral oil, dimethyl sulfone (3.8 g.) and dimethyl sulfoxide (18 ml.) were heated at 55 C. for one hour with stirring. After the reaction mixture was cooled to 50 C., methyl 3,4,.5-triethylbenz0ate (4.6 g.) was added and the mixture heated at 60 C. for 1% hours. The mixture was poured over ice and acidified to give crude methyl 3,4,S-triethylbenzoylmethyl sulfone (5.5 g.) M.P. 125126 C. after recrystallization from ethanol.

A slurry of crude methyl 3,4,S-triethylbenzoylmethyl sulfone (4.5 g.) in ethanol (3 ml.) and water (10 ml.) was stirred at room temperature while sodium borohydride (0.2 g.) in water (4 ml.) was added over about 15 minutes. The reaction mixture was stirred for an additional 1 /2 hours, cooled to +2 C., filtered, and the collected solids washed with ice water to give crude methyl fl-hydroxy-B-(3,4,5-triethylphenyl)ethyl sulfone (3.7 g.). This melted at 101-102 C. after recrystallisation from ethyl acetate.

A mixture of methyl B-hydroxy-B-(3,4,5-triethylphenyl)ethyl sulfone (2.83 g.), B-anilinoproionitrile (1.65 g.), dimethyl sulfoxide (4 ml.) and potassium tertiary butoxide (1.13 g.) in tertiary butanol (8.3 ml.) was heated at 48 C. for 1 /2 hours and then poured into ice water to give a-(3,4,S-triethylbenzyl)-;9-anilinoacrylonitrile (3.7 g.), M.P. 154156 C. after recrystallization from ethanol.

A mixture of a-(3,4,5-triethylbenzyl)-B-anilinoacrylonitrile (3.2 g.), guanidine hydrochloride (2.9 g.), and sodium methylate (2.2 g.) in ethanol (40 ml.) was heated at reflux for 25 hours. About one-third of the solvent was boiled off and the remaining reaction mixture cooled. The resulting solid was removed by filtration, and recrystallized from acetone. This provided 2,4-diamino (3',4,5'-triethylbenzyl)pyrimidine (1.1 g.), M.P. l75l76 C.

10 EXAMPLE 2 3,4,5-triethylbenzoic acid is treated with an excess of thionyl chloride and then reduced to 3,4,5-triethylbenzaldehyde under Rosenmund conditions. The aldehyde is condensed with B-methoxy-propionitrile in methanol containing an excess of sodium methoxide to give u-(3,4,5-triethylbenzyl)- 8-B-dimethoxypropionitrile. This is then heated at reflux with guanidine hydrochloride in methanolic sodium methylate to give the 2,4-diamino-5-(3',4,5'- triethylb enzyl) pyrimidine.

EXAMPLE 3 3,4,5-triethylbenzaldehyde is condensed with fl-anilinopropionitrile in dimethyl sulfoxide containing potassium tertiary butoxide in tertiary butanol at about 55 C. for about 2 hours to give a-(3,4,.5-triethylbenzyl)- 8-anilinoacrylonitrile which is converted to the 2,4-diamino-5-(3', 4',5-triethylbenzyl)pyrimidine as in Example 1.

EXAMPLE 4 p-Methylacetophenone is alkylated with ethyl bromide in a Friedel-Crafts reaction to give 4-methyl-3,5-diethylacetophenone. This is oxidized to 4-methyl-3,5-diethylbenzoic acid by sodium hypochlorite. The acid is esterified under Fischer conditions. The ester is converted to 5- (4-methyl-3',5'-diethylbenzyl) 2,4 diaminopyrimidine according to theh procedures of Example 1.

EXAMPLE 5 4-ethylacetophenone is alkylated in a Friedel-Crafts reaction with isopropyl bromide to give 4-ethyl-3,5-di-isopropylacetophenone which is then treated as in Example 4 to finally yield 5-(4'-ethyl3',5-di-isopr0pylbenzyl)-2,4- diaminopyrimidine.

EXAMPLE 6 2,6-diethyl 4 (N,N-dimethylaminomethyl)phenol is pared by reacting 2,6-diethylphenol (itself prepared by bydrolyzing the diazonium salt of 2,6-diethylaniline) with formaldehyde and dimethylamine.

To a stirred solution of sodium methylate (0.64 g.) in ethylene glycol (225 ml.) was added 2,6-diethyl-4-(N,N- dimethylaminomethyl)phenol (24.5 g.) and 2,4-diaminofi-methylthiopyrimidine (19.5 g.). The reaction mixture was heated at -150 for 3 hours, cooled, and added to water. A yellow gum separated. This was dissolved in acetone, acidified with hydrochloric acid, and heated on a steam bath. A solid separated, which was extracted with ethyl acetate and ether, followed by recrystallization from acetone/methanol, with the aid of charcoal. The product, 2,4-diarnino-5-(3Q5' diethyl-4'-hydroxybenzyl)- G-methylthiopyrimidine hydrochloride, M.P. 210 212 C. (dec.), was obtained in a 60% yield.

A solution of this pyrimidine (3.0 g.) and sodium methylate (0.91 g.) in dimethyl sulfoxide (32 ml.) was cooled in an ice bath and methyl iodide (0.58 ml.) added. The mixture was stoppered and maintained at room temperature for 24 hours, after which the solvent was removed. The gum was extracted with sodium hydroxide to remove any phenolic material, and then dissolved in ethanol and converted to a hydrochloride salt by the addition of hydrochloric acid. The resultant solid was recrystallized from ethanol, which produced 2,4-diamino-5-(3',5-diethyl-4'-methoxybenzyl)-6-methylthiopyrirnidine hydrochloride (1.5 g.), melting at 215-218 C.

A 1.0 g. portion of this product in 75 ml. of ethanol was heated under reflux, and 7.5 g. of freshly activated Raney nickel added over a 2.5 hour period. Stirring and heating were continued for an additional 9 hours, after which the Raney nickel was filtered off and washed with ethanol. The solution was evaportaed to dryness and recrystallized from ethanol-ether, with the aid of charcoal, thus producing 2,4 diamino-5-(3',5'-diethyl-4-methoxybenzyl)pyrimidine (0.2 g.) as white platelets melting at 153-154 C., and having the correct elementary analysis. UV maxima were at 270 nm. (cation) and at 287 nm. (neutral species).

EXAMPLE 7 A mixture of N,N-dimethyl-3,5-di-isopropyl-4-hydroxybenzylamine (23.5 g.) [Coffield et al., J. Am. Chem. Soc., 79, 5019 (1957)], 2,4 diamino-6-methylthiopyrimidine (15.6 g.) sodium methoxide (0.60 g.) and ethylene glycol (125 ml.) was treated in a manner similar to that of Example 6 to produce 2,4-diamin-5-(3,5-di-isopropyl-4-hydroxybenzyl)-6-methylthiopyrimidine; yield, 29 g. crude product (85%). The product was purified by conversion to the hydrochloride salt with ethanol plus hydrochloric acid, and then recrystallized from ethanol; UV maxima at pH 12 were at 296 and 211 nm.; at pH 2 maximia were found at 302 and 200 nm. [Anal. Calcd. for

C, 56.45; H, 7.11; N, 14.63. Found: C, 56.25; H, 7.05; N, 14.57.]

The above product (25 g.) was treated with methyl iodide (10.6 g.) using the procedure of Example 6, which produced 2,4 diamino-5-(3',5'-diethyl-4-methoxybenzyl)-6-methylthi0pyrimidine hydrochloride (13 g.) melting at 280 (dec.). [Anal. Cald. for C H N OS-HCl: C, 57.48; H, 7.36; N, 14.11. Found: C, 57.70; H, 7.39; N, 14.19.]

Three grams of this product was dissolved in 50 ml. of hot ethanol and heated under reflux with approximately 30 g. of activated Raney nickel for hours. The course of the reaction was followed by observing the change in UV maximum in acid from 307 to 272 nm. The nickel was then separated from the hot solution, and the filtrate concentrated to yield 1 g. (43%) of 2,4-diamino-5-(3',5'- di-isopropyl-4'-methoxybenzy )pyrimidine, which melted at 205-207 after recrystallization from ethanol. [Anal. Calcd. for C H N O: C, 68.76; H, 8.34; N, 17.82. Found: C, 68.76; H, 8.43; N, 17.67.]

EXAMPLE 8 N,N dimethyl-3,5-di-t-butyl 4 hydroxybenzylamine (5.06 g.) [Coflield et al., J. Am. Chem. Soc., 79, 5019 (1957)] was reacted with 2,4-diamino-6-methylthiopyrimidine (3.0 g.) by the method of Example 6 to produce 2,4-diamino-5-(3',5-di-t-butyl-4-hydroxybenzyl)-6- methylthiopyrimidine, 5.3 g. (67%). The product was purified as the hydrochloride by recrystallization from ethanol; M.P. 218221.5.

This product was treated with methyl iodide as in Example 6 to produce 2,4-diamino-5-(3,5-di-t-butyl-4'-methoxybenzyl)-6-methylthiopyrimidine hydrochloride, M.P. 215216, from ethanol-ethyl acetate. [Anal. Calcd. for C H N OS-HCl: C, 59.33; H, 7.82; N, 13.18. Found: C, 59.70; H, 7.85; N, 13.14.]

The methylthio group was removed from the above pyrimidine by treatment with Raney nickel, as described in Example 6. There was obtained 2,4-diamino-5-(3',5'-di-tbutyl4-methoxybenzyl)pyrimidine in 56% yield. The product, when purified as the hydrochloride by recrystallization from ethanol, melted at 272-275. [Ana]. Calcd. for C H N O-HCl: C, 63.39; H, 8.25; N, 14.78. Found: C, 63.39; H, 8.35; N, 14.70.]

2,6-di n propylphenol [Claisen, Ann., 418, 92] is treated with formalin and dimethylamine in ethanol according to the procedure of Coflield et al. [J Am. Chem. Soc., 79, 5019 (1957)] for the isopropyl analog, to yield N,N-dimethyl-3,5-di-n-propyl-4-hydroxybenzylamine.

A mixture of 2,4-diamino-6-methylthiopyrimidine, an equivalent amount of N,N-dimethyl-3,5-di-n-propyl-4-hydroxybenzylamine, and 0.1 equivalent of sodium methylate is heated in ethylene glycol in an atmosphere of nitrogen at for 3 hours. Most of the glycol is then removed under vacuum, and the residue is diluted with several volumes of water, followed by neutralization with acetic acid. There is thus obtained 2,4-diamino-5-(3',5'-din-propyl 4' hydroxybenzyl) 6 methylthiopyrimidine, which may be purified by conversion to its hydrochloride and recrystallization from ethanol. The hydrochloride salt is dissolved in dimethyl sulfoxide, followed by the addition of 2 equivalents of sodium methylate to produce the sodium salt of the phenol. This is followed by the addition of 1 equivalent of methyl iodide. The solution is allowed to stand in a stoppered flask for 48 hours, after which the dimethyl sulfoxide is removed under vacuum. The residue is extracted with warm dilute sodium hydroxide to remove any phenolic material. The insoluble solid is isolated and washed well with water. This product, 2,4-diamino-5- (3,5 di n propyl-4-methoxybenzyl)-6-methylthiopyrimidine, is then dissolved in hot ethanol, and active Raney nickel (6-10 times the weight of the pyrimidine) added. The mixture is stirred and heated under reflux for several hours. The course of the dethiation is observed by the change in ultraviolet absorption spectrum, which is characterized by a loss in UV maximum at 307 nm. When the reaction is completed, the nickel is filtered off, and the ethanol concentrated to small volume and chilled. There is thus obtained 2,4-diamino-5-(3',5-di-n-propyl-4- methoxybenzyl)pyrimidine. The product may be purified by conversion to its hydrochloride salt, followed by crystallization from ethanol.

EXAMPLE 10 2,4 diamino 5 (3',5' diethyl-4'-hydroxybenzyl)-6- methylthiopyrimidine [see Example 6] is alkylated with n-octyl bromide in dimethyl sulfoxide in a manner similar to Example 6, except that the reaction mixture is heated on the steam bath overnight. There is thus obtained 2,4- diamino 5 (3,5 diethyl-4'-octyloxybenzyl)-6-methylthiopyrimidine, which is dethiated with Raney nickel according to the procedure of Example 6 to produce 2,4- diamino-S- (3 ,5 -diethyl-4'-octyloxybenzyl) pyrimidine.

What is claimed is:

1. A compound of Formula I or a pharmaceutically acceptable salt thereof wherein R and R are the same or different and each is an alkyl group having from 2 to 4 carbon atoms, and R is an alkyl or alkoxy group having from 1 to 12 carbon atoms.

2. A compound according to claim 1 which is 2,4-diamino-S- (3 ',4',5 '-triethylb enzyl pyrimidine.

3. A compound according to claim 1 which is 2,4-diamino-S- 4'-methyl-3 ,5 diethylbenzyl) pyrimidine.

4. A compound according to claim 1 which is 2,4-diamino-5- (4-ethyl-3 ',5-di-isopropylbenzyl pyrimidine.

5. A compound according to claim 1 which is 2,4-diamino-S- (3 ,5 -diethyl-4'-methoxybenzyl) pyrimidine.

6. A compound according to claim 1 which is 2,4-diamino 5 (3,5' di-isopropyl-4'-methoxybenzyl)pyrimidine.

7. -A compound according to claim 1 which is 2,4-diamino 5 (3,5' di t butyl-4'-methoxybenzyl)pyrimidine.

13 14 8. A compound according to claim 1 which is 2,4-di- References Cited amino 5 (3',5'-dipropy1-4'-methoxybenzyl)pyrimidinc. UNITED STATES PATENTS 9. A compound according to claim 1 WhlCh 1s 2,4-d1- 2,658,897 11/1953 Hitchings et a1 260 25,6 4

amino-S- (3 ',5diethy1-4-octy1oxybenzyl) pyrimidine.

10. A compound according to claim 1 Where R has 5 RICHARD J, GALLAGHER, Primary Examiner 1 to 8 carbons.

11. A compound according to claim 1 in which R has us l to 4 carbon atoms. 260240 R, 256.4 C, 256.5 R, 415 E; 424251 

